NUDT15 genotyping during azathioprine treatment in patients with inflammatory bowel disease: implications for a dose-optimization strategy. (26th June 2020)

• Record Type: Journal Article
• Authors: Xu, Ye; Qiao, Yu-Qi; Li, Han-Yang; Zhou, Mi; Cai, Chen-Wen; Shen, Jun; Ran, Zhi-Hua
• Is Part Of: Gastroenterology report. Volume 8:Number 6(2020)
• Page Start: 437
• Page End: 444
• Publication Date: 2020-06-26
• Subjects: NUDT15 -- azathioprine -- inflammatory bowel disease -- toxicity -- efficacy; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1093/gastro/goaa021
• Languages: English
• ISSNs: 2052-0034

Abstract

Abstract: Background: NUDT15 R139C is an Asian-prevalent genetic variant related to azathioprine (AZA) intolerance in patients with inflammatory bowel disease (IBD). However, it remains unclear how to utilize the genotyping results to improve the step-up dosing strategy with an already low starting dose in Asian practice. Methods: Clinical data of eligible IBD patients who received AZA therapy and NUDT15 R139C testing were retrospectively collected. The relationship between NUDT15 genotype, AZA doses, and AZA-induced toxicity and efficacy were comprehensively analysed. Results: A total of 159 patients were included for toxicity analysis. Compared with the wild genotype, patients heterozygous for R139C are more prone to developing myelotoxicity and alopecia ( P = 0.007; P = 0.042). In particular, they had a 5.4-fold risk of developing myelotoxicity when AZA dosage was increased from 25 mg/d to 50 mg/d ( P < 0.001). Regarding efficacy, 115 patients who had received AZA for >4 months and maintained clinical remission on AZA monotherapy were included for further analysis. R139C heterozygotes were finally titrated to a significantly lower dose than the wild genotype [median (interquartile range): 0.83 (0.75–0.96) vs 1.04 (0.89–1.33) mg/kg/d, P = 0.001], whereas the clinical remission rates did not differ between groups ( P = 0.88). Conclusions: IBD patients with R139C heterozygote are highly susceptible to AZA-induced myelotoxicity at an escalated dose of 50 mg/d. Thus, they may require a smaller dose increase after a starting dose of 25 mg/d. The final target dose of these patients could be set lower than that of the wild genotypes without compromising efficacy.